This Program Project is comprised of Clinicians, Clinician/Scientists, and Basic Scientists working to bring together the scientific and clinical resources needed to investigate directly in humans or in human tissues the effects of toxic substances in the environment. This departure from standard approaches to investigation of the toxicology of environmental agents is based on the recognition that the relevance to man of toxicity testing in animals or in vitro systems can be established with certainty only by making critical experiments on humans or on human derived tissues. In Project #1 the characteristics and distribution among human liver samples of purified human liver cytochromes P-450 in patients. Project #3 proposes to use similar biochemical and molecular biologic techniques to investigate a human liver aldo-keto reductase involved in the metabolism of the organochlorine pesticide, chlordecone. In Project #4, biochemical and cytological probes will be used to investigate the mechanisms of toxicity of organophosphates on the nervous system. In Project #5, biochemical and micropuncture techniques will be used to examine mechanisms of glomerular vs. tubular injury by metals. Project #6 is the Clinical Research Core comprised of medical specialty units (neuro-psychiatric, pulmonary, cardiovascular, liver, renal, dermatology, urology, analytical laboratories) capable of evaluating organ specific toxicity. The Core also is comprised of patient populations available for investigation. These include workers with documented over-exposure to cadmium and patients with documented allergic dermatitis to environmental agents. The proposed studies are expected to provide new information about clinical manifestations of toxicity due to environmental agents, insight into the mechanism of injury by these agents, and a greater understanding of some detoxification of enzyme systems. Moreover, we expect this Program to exemplify the utility involving clinical medicine in the study of human toxicology.